Murine ecotropic leukemia viruses (MuLV-E) are Type C retroviruses whose host range is restricted to mice and rats at the cellular receptor. This subgroup of retroviruses is composed of heterogeneous collection of viruses that utilize a common receptor for entry into host cells and induce disorders varying from T-and B-cell lymphomas and myeloid leukemias to immunodeficiency disorders such as frequently precede onset of neoplasia in animals infected with oncovirus and spongiform encephalomyelopathy with hind limb paralysis. Interactions of the viral envelope proteins have been implicated as directly causative or as accelerating factors in viral pathogenesis. The cell surface receptor mediating MuLV-E entry, encoded by the Atrc-1 gene, functions as the principal transporter of cationic amino acids. Genetic analyses revealed the involvement of the third extracellular domain of ATRC1 in retrovirus entry as the putative virus binding site, and two residues within it that constitute the principal cellular determinant of ecotropic virus host range between mouse and man. Surprisingly, the determinant requires an acidic and a nearby hydrophobic amino acid for efficient ecotropic virus entry, a motif that is similar to a critical component of the binding sites of the HIV receptor, the subgroup A avian leukosis virus receptor, and possibly of the gibbon ape/subgroup B feline leukemia virus receptor, suggesting that at least the initial step of retrovirus entry may be governed by a common mechanism. The immediate goals of this study are to (1) identify all the residues within the third extracellular domain of ATRC1 required for efficient virus entry and determine their role in virus binding and entry using site- directed mutagenesis, infection assays and biochemical analyses of virus binding and fusion, (3) determine if the third extracellular domain of the receptor is the sole critical component of the receptor in virus binding and entry, and (4) identify the specific residues on viral proteins which interact with these essential receptor regions by examining virus variants that have adapted for more efficient utilization of receptor mutants. The long term goals of the proposed research are to determine(i) the role interactions mediating entry may play in viral oncogenesis, (ii) which aspects of the mechanism of entry are unique to ecotropic retroviruses and which aspects can be extended to describe entry by non-ecotropic retroviruses or by other mammalian viruses, and (iii) if possible anti-viral therapeutic strategies can be devised from the knowledge acquired on virus entry.